Outcomes of Chylothorax Nonoperative Management After Cardiothoracic Surgery: A Systematic Review and Meta-Analysis

Introduction Chylothorax after thoracic surgery is a severe complication with high morbidity and mortality rate of 0.10 (95% confidence interval [CI] 0.06 – 0.02). There is no agreement on whether nonoperative treatment or early reoperation should be the initial intervention. This systematic review and meta-analysis aimed to evaluate the outcomes of the conservative approach to treat chyle leakage after cardiothoracic surgeries. Methods A systematic review was conducted in PubMed®, Embase, Cochrane Library Central, and LILACS (Biblioteca Virtual em Saúde) databases; a manual search of references was also done. The inclusion criteria were patients who underwent cardiothoracic surgery, patients who received any nonoperative treatment (e.g., total parenteral nutrition, low-fat diet, medium chain triglycerides), and studies that evaluated chylothorax resolution, length of hospital stay, postoperative complications, infection, morbidity, and mortality. Central Message Nonoperative treatment for chylothorax after cardiothoracic procedures has significant hospital stay, morbidity, mortality, and reoperation rates. Results Twenty-two articles were selected. Pulmonary complications, infections, and arrhythmia were the most common complications after surgical procedures. The incidence of chylothorax in cardiothoracic surgery was 1.8% (95% CI 1.7 – 2%). The mean time of maintenance of the chest tube was 16.08 days (95% CI 12.54 – 19.63), and the length of hospital stay was 23.74 days (95% CI 16.08 – 31.42) in patients with chylothorax receiving nonoperative treatment. Among patients that received conservative treatment, the morbidity event was 0.40 (95% CI 0.23 – 0.59), and reoperation rate was 0.37 (95% CI 0.27 – 0.49). Mortality rate was 0.10 (95% CI 0.06 – 0.02). Conclusion Nonoperative treatment for chylothorax after cardiothoracic procedures has significant hospital stay, morbidity, mortality, and reoperation rates.


INTRODUCTION
Chyle is an opaque, milky-white fluid consisting mainly of emulsified fats that pass through the lacteals of the small intestines into the lymphatic system [1] .This fluid contains lipids, proteins, immunoglobulins, lymphocytes, vitamins, and electrolytes [2] .Chyle leak is a potentially devastating phenomenon and may impair nutrition, compromise and delay wound healing, and prolong hospitalization [3] .Postoperative chylothorax is usually caused by injuries to the thoracic duct or to its tributaries during surgery [4] .Chylothorax may happen in several types of cardiothoracic surgery, including esophagectomy, lobectomy, cardiac procedures, and mediastinal tumors resection [5][6][7][8][9] .The diagnosis of chylothorax consists of Brazilian Journal of Cardiovascular Surgery evaluating triglyceride levels, cholesterol values, and microscopy crystals [10] .Reoperation with thoracic duct ligation, with direct closure of the ruptured lymph vessel or with thoracic duct obliteration, is one of the treatment choices for this complication [11,12] .Other therapeutic approaches to treat chylothorax comprise lymphangiography with thoracic duct embolization [13] .However, nonoperative management of postoperative chylothorax (NMPC) is usually considered the first approach, and it is a non-invasive strategy based on prolonged fasting or a low-fat diet.The central idea is to reduce the lymphatic system content to progressively lower the lymphatic leak flow [14] .NMPC comprises total parenteral nutrition (TPN) and oral or enteral medium-chain triglycerides (MCT) [15] .Currently, there is no scientific consensus regarding the optimal management of chylothorax after cardiothoracic surgeries.Consequently, the present review aims to evaluate the outcomes of conservative management of postoperative chylothorax.

Protocol Register
This systematic review and meta-analysis was submitted to the International Prospective Register of Systematic Reviews (or PROSPERO) [16] under the trial registry CRD42021235243.Search strategy and selection articles were based on the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (or PRISMA) guideline [17] .

Search and Selection
Two researchers carried out, independently, the search and selection of the evidence in the following scientific databases: PubMed®, Embase, Cochrane, and LILACS (Biblioteca Virtual em Saúde); manual search evaluating the references of primary studies and other reviews was done.

Data Extraction
The following data were extracted from the studies: (1) general information (authors, year of publication, study design); (2) patients and chylothorax specifications (total patients, cardiothoracic procedure, patients with chylothorax, chylothorax definition, and mean age); (3) conservative treatment; (4) variables related with population and outcomes (chest time maintenance, reoperation, morbidity, complications, length of hospital stay, mortality).

Risk of Bias and Certainty Assessment
The articles were assessed for bias risk using the Risk of Bias in Non-Randomized Studies of Intervention (ROBINS-I) [18] assessment tool.Grading of Recommendations, Assessment, Development and Evaluations (GRADE) (https://www.gradepro.org/) [19]was used to evaluate the quality of the evidence.

Synthesis and Statistical Analysis
The authors extracted and analyzed the absolute numbers for each outcome using the software Comprehensive Meta-Analysis.The measures used to express benefit and harm varied according to the outcomes and were expressed by continuous variables (mean and standard deviation [SD]) or by categorical variables (absolute number of events).In continuous measures, the results were mean difference and SD.The results were synthesized in a meta-analysis.The heterogeneity of effect sizes among studies was assessed with I 2 statistics.Pooled-effect measures were calculated with 95% confidence interval (CI), and the significance level used was 0.05.

Baseline Characteristics of the Included Studies
After applying eligibility criteria, 22 studies were selected for qualitative and quantitative analysis [14, . The seection flow diagram is shown in Figure 1.Included studies comprised 497 patients with chylothorax, with a mean age of 50.19 years old.Baseline characteristics of the included studies are reported in Table 1.The cardiothoracic procedures performed included: esophagectomy, lobectomy, gastrectomy, congenital heart surgery, trauma treatment, miscellaneous thoracic procedure, aortic surgical procedure, pulmonary resection, mediastinal mass resection, cardiac surgery, mediastinoscopy, and sympathectomy.

Complications
The most common complications in patients undergoing nonoperative management of chylothorax were pulmonary complications (respiratory failure and pneumonia), infections, and arrhythmia.Other complications after surgical procedure comprised urinary tract infection, the necessity of prolonged ventilation, prolonged air leak, cervical anastomotic leak, reintubation, renal failure, sepsis, empyema, acute hemorrhagic pseudocyst, delirium, mediastinal chyloma, atelectasis, and seizure.

Chest Tube
Twelve studies analyzed the length of chest tube usage in patients undergoing nonoperative management of chylothorax.The mean time of chest tube maintenance was 16.08 days (95% CI 12.54 -19.63) (Figure 3).

Length of Stay
The mean length of hospital stay was 23.74 days (95% CI 16.08 -31.42) for patients undergoing nonoperative management of chylothorax after cardiothoracic procedures (Figure 4).

Risk of Bias and Certainty Assessment
The GRADE critical appraisal showed that most outcomes presented low or very low certainty assessment.The main reasons for the reduced certainty were due to risk of selection bias, clinical heterogeneity among studies (comprising a variety of surgical procedures), and imprecision of data synthesis for some outcomes (Supplementary File 1).ROBINS-I tool showed that the main concerns were risk for selection bias and classification of the intervention (Supplementary File 2).

DISCUSSION
NMPC as the first approach strategy for chylothorax is associated with a high risk for morbidity and mortality, with prolonged hospital stay and time of chest tube.More than one-third of the patients undergoing nonoperative management will require reoperation.

Reoperation method
Guillem et al [29]  Marts et al [32] 1992 Alexiou et al [20]  Bolger et al [22]  Brazilian Journal of Cardiovascular Surgery Bonavina et al [23]  Cerfolio et al [24]  Dugue et al [26] 1998 Lagarde et al [30] 2005 Seow et al [35]  Shah et al [36] 2012 Shen et al [37]  Petrella et al [14]  Furukawa et al [28] 2018 Cohort 818 Pulmonary resection 14 Uninformed Uninformed TPN; low-fat diet Uninformed Takuwa et al [39]  Brazilian Journal of Cardiovascular Surgery Chan et al [25] 2005 Fahimi et al [27] 2001 fibrin glue Shimizu et al [38]  Worthington et al [40] 1995 Cohort Uninformed Penetrating chest trauma  Since chylothorax is a rare complication after cardiothoracic surgery (incidence rate = 1.8%), trials comparing the treatment options with a satisfactory sample size are difficult to be performed.There is no consensus on the time required for the decision to operate on the patient after a failing nonoperative initial management [14,20] .Consequently, it is impossible to provide the highest standard of evidence-based recommendation for any treatment approach.However, considering the high morbidity and mortality, length of hospital stay, and demand for reintervention, it is reasonable to consider early reoperation after a chylothorax diagnosis in postoperative cardiothoracic procedures.Only future studies that compare nonoperative methods and early invasive intervention for the management of chylothorax will allow a definitive answer.Merigliano et al. [33] assessed chylothorax outcomes after esophagectomy and advocated for early reoperation with thoracic duct ligation.The authors found high morbidity with a high rate of demand for reoperation after initial treatment with TPN without oral diet intake.Besides, no reliable predictive variables for the success of the nonoperative management were found.Wemyss-Holden et al. [41] also defend an aggressive early intervention for postoperative chylothorax within 48 hours from the diagnosis.The idea is to act as early as the patient remains relatively fit, without nutritional and immunological debilitation.Besides, early reoperation decisions allow low adherence and better tissue visualization, facilitating direct closure of the thoracic duct injury [42] .Prolonged and constant chyle drainage through the chest tube will lead patients to nutritional deficit and immunological depletion, which will make them vulnerable to hospital-acquired infections [43] .The chyle contains a large amount of T lymphocytes and transports immunoglobulins and cytokines.Continuous fluid leakage ends up impacting both the primary response [44] and the humoral response to pathogens [33] .Besides, proper gradients guide proteins, peptides, macromolecules, nutrients, cells, and chemokines' migration to the tissues, establishing the correct Brazilian Journal of Cardiovascular Surgery Fig. 7 -Reoperation rate after initial nonoperative management of postoperative chylothorax.CI=confidence interval.
direction of interstitial-lymphatic capillaries flow.Therefore, chyle depletion will impair patients' capacity to combat pathogens and regulate inflammation [45] .Besides, chyle also contains fat-soluble vitamins, proteins, electrolytes, and water, and consequently, chylothorax leads to hyponatremia, hypokalemia, and acidosis.The caloric loss in chyle pleural effusion rapidly induces severe protein-calorie malnutrition [46] .Of patients undergoing NMPC for chylothorax, 37.1% will fail and require reintervention to obliterate the thoracic duct.The video-assisted thoracic duct ligation is probably the most applied reintervention technique [23,27,30,31,33,34] .During reoperations, one of the main difficulties is to find the site of lymphatic duct injury.Delayed intervention may create a field with intense inflammatory adherences, making it difficult to spot the site of injury.The administration of an oral cream containing long-chain triglycerides before surgery may help to find the spot of chyle leakage in the lymphatic duct [14,27,29] .Another alternative to obliterating thoracic duct systems is with interventional radiology.Lymphangiography is used to find the leak spot with subsequent embolization [11] , reducing the chyle drainage [47] .Prolonged fasting with TPN aims to reduce the amount of chyle produced, helping recover the ruptured duct [14] .Parenteral nutrition has some inherent risks that should be taken into accounts, such as catheter-related bloodstream infections, venous thrombosis, and integrity loss of the gastrointestinal mucosa [48] .The central line complications may contribute to the high expected morbidity in NMPC.The compromised immunological status in chylothorax patients associated with the risk for bloodstream infection raises their mortality risks.
To reduce the risk of central line-associated bloodstream infections and other central line-associated complications, an alternative within the NMPC strategies is the MCT diet.By replacing the long-chain triglycerides for MCT supplementation, the amount of chyle produced would be reduced and, consequently, the loss of fluid and nutrients from the chylothorax [29] .MCT is absorbed directly into the blood, avoiding the overload of the lymphatic system.MCTs are easily ingested, rapidly absorbed, and readily metabolized directly into the portal venous system by passing the thoracic duct lymphatic system [49] .However, either by TPN or MCT therapy, it is expected to take a prolonged time for the injured lymphatic system to heal, imposing a prolonged time of thoracic tube usage, prolonged hospital stay, and increased hospital resources usage and inherent costs.Unlike blood vessels, chyle lacks coagulation factors and platelets, explaining the long time for the spontaneously leak flow reduction [50] .
Long-term chest tube use generates additional risks.Patients with prolonged use of chest tubes will face breath discomfort and higher demand for analgesics.The chest tube may also impair rib cage expansion, leading these patients to atelectasis, pleural effusion, and pneumonia [51] .Tube displacement, with subsequent emphysema and pneumothorax, may also occur, contributing to the increased risk of morbidity and mortality for patients [52][53][54] .
This systematic review presents the current evidence for chylothorax nonoperative management.Knowing the expected outcomes for nonoperative management, as shown in this metaanalysis, caregivers are able to expand their knowledge about this matter to make the best decisions for their patients.The poor outcomes of this strategy point that early reoperation may be an interesting alternative for chylothorax after cardiothoracic surgery.

Limitations
The present study has some limitations.The concept of chylothorax is not homogeneous across the studies, with different definitions.The nonoperative methods for treating chylothorax are also variable across the studies, comprising different types of nutrition and time to decide to perform the reintervention.In addition, it must be considered that a chylothorax is a rare event and that the available studies do not have a large sample size to determine the level of evidence in this theme.The findings of the present  Brazilian Journal of Cardiovascular Surgery study outlined the need for future controlled trials that compare nonoperative methods with early reoperation to verify the best treatment option for chylothorax after cardiothoracic surgery.

CONCLUSION
Nonoperative treatment for chylothorax after cardiothoracic procedures has significant hospital stay, morbidity, mortality, and reoperation rates.

No financial support. No conflict of interest.
MFO Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; drafting the work; agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved; final approval of the version to be published MCAS Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved; drafting the work; final approval of the version to be published FT Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; revising the work critically for important intellectual content; agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved; final approval of the version to be published The selection was completed in July 2022.The search strategy on MEDLINE® was: (Lymphatic fistula OR Lymphatic leak OR Lymphatic fistulae OR Chyle leak OR Chylous ascites OR Chyloperitoneum OR Chylous Peritonitis OR Chylothorax OR Thoracic duct OR Duct, Thoracic OR Cisterna Chyli OR Cisterna Chylus OR Lymphatic vessels OR Lymphatic Venule) AND (Diet, fat restricted OR Diet low fat OR Diet Fat Free) AND (Nutrition, Parenteral OR Parenteral Feeding OR Intravenous Feeding).Similar terms were used in the other databases.
strawcoloured fluid from the chest drain continued for > 5 days and it was confirmed as a chylous leak by its milky white appearance following the administration of 110 mg/dl or greater and the presence of chylomicrons in the pleural fluid in all patients 65 TPN; MCT Duct ligation pleural fluid had to be 1.2 mmol/L, with a total cell number 1,000 cells/mL and a predominance of mononuclear cells 1 TPN; low-fat diet Duct ligation
of Bias in Non-Randomized Studies of Interventions (ROBINS-I) assessment tool for cohort-type studies.

Table 1 .
Baseline characteristics of the included studies Autor